This proposal is for a career development award that will allow my transition from studying genetics in Drosophila as a graduate student and neuroendocrine stress pathways as a post-doctoral fellow, to a research focus on Alzheimer's disease (AD), while continuing to pursue a career goal of establishing an independent research program. I have been graciously accepted for training by my mentor on this proposal, Dr. Hui Zheng, who, through an interest in stress phenotypes in human AD and mouse models of AD recruited me to work in her lab to investigate these phenotypes. The environment is ideal for this project due to the proximity of a behavioral core facility, and the expertise of its Director and a co-mentor on this proposal, Dr. Rich Paylor. In addition, Baylor College of Medicine is located within the Texas Medical Center, and I will have access to training in clinical issues surrounding human patients that suffer from AD with consultants on the proposal Dr. Rachelle Doody and a neuropathologist, Dr. J Clay Goodman. From this excellent group of well established scientists, I will receive the best training in cellular, behavioral, and clinical approaches to the study of Alzheimer's disease while maximizing my past training by investigating the disruption of neuroendocrine stress pathways in the development and progression of AD. Alzheimer's disease is understood as a disease of neuronal degeneration that can incapacitate its victim through the loss of memory, bodily function, and livelihood. While much progress has been made in understanding how memory formation and retention is lost in AD patients, less is known about how endocrine circuits become mis-regulated as neurons are lost. One of these endocrine circuits that is known to be disrupted in AD patients is the Hypothalamic-Pituitary-Adrenal (HPA) axis which controls cortisol release in response to stress. In this proposal, I detail a set of experiments that will provide information about how neuronal systems that respond to stress and control the activity of the HPA axis are mis-regulated in an AD mouse model, and how stress impacts the progression of AD related pathology. The experimental approach will be three fold. First, I plan to characterize aging mice carrying Familial Alzheimer's Disease (FAD) mutations that acquire AD pathologies, for changes in anxiety related behavior, HPA axis function, and molecular gauges of stress system regulation. These observations will allow me to determine the degree to which susceptibility and acquisition of AD pathologies alters stress axis function. Second, I will apply stressors to model animals, and determine how this changes measures of AD related pathology, such as amyloid plaque formation, neurofibrillary tangle-like pathology, and neuronal degeneration. In the third aim, I will genetically and pharmacologically ablate activity of the HPA axis, and determine if this ameliorates the progression of AD pathologies and cognitive decline. The experiments described in this proposal draw from my experience with Drosophila and mouse genetics and my work in the field of stress neuroendocrinology. Funding of this proposal will allow me to gain new training in the field of Alzheimer's Disease research, and acquire skills in neuropathological analysis and behavioral characterization of AD. Taken together, this proposal describes a training and research plan that will guide my career to the next level, and allow me to smoothly transition to an independent research position while establishing a research program on the stress biology of AD. PUBLIC HEALTH RELEVANCE: This project will study whether increased stress leads to Alzheimer's Disease, and the role that stress has in the progression of the disease. The results of this study will contribute to the development of new therapies for Alzheimer's disease as well as a better understanding of how to use currently available stress lowering medication in treating Alzheimer's Disease.